Integrated Biobehavioral Analysis of Sex Differences in a Rat Model of Schizophrenia

Abstract

Schizophrenia is a mental illness affecting roughly 1% of the population that is characterized by both positive/affective and negative/cognitive symptoms and is associated with abnormalities in multiple neurotransmitter systems and brain areas. Recently, reduced function of the N-methyl-D-aspartate receptor (NMDAR) has emerged as an etiologic hypothesis with explanatory power for this spectrum of disturbances. However, it is unknown how NMDAR hypofunction relates to the striking sex differences that are also seen in the incidence and severity of schizophrenia's positive (female > male) vs. negative (male > female) signs, in its associated neurochemical imbalances and in the efficacies of drugs commonly used to treat patients. To approach these questions, my dissertation explored whether a rodent model of NMDAR hypofunction recapitulates sex differences in behavior, drug response and neurochemistry that mirror those in schizophrenia. The first studies probed behavioral sequelae of NMDAR hypofunction in adult male and proestrus female rats and found that females had increased startle responses, locomotor activity, ataxia, and emitted more spontaneous vocalizations indicative of negative affect which are positive symptom correlates, while males had greater deficiencies in prepulse inhibition, rearing and grooming which are models for schizophrenia's negative signs. Further, the typical neuroleptic haloperidol was more effective in attenuating positive but not negative symptom correlates and was more effective in females while the atypical neuroleptic clozapine attenuated both positive and negative symptom correlates in both sexes but was slightly more effective on negative symptom correlates in males. The second set of studies used microdialysis and magnetic resonance spectroscopy (MRS) to explore whether NMDAR antagonism produces sex-specific changes in amine and amino acid neurotransmitter levels in the prefrontal cortex in-vivo. Both studies had their caveats; locomotor activity confounded quantification of drug effects via microdialysis and while MRS showed promise in quantifying levels of both classes of neurotransmitters, paroxysmal apnea induced by NMDAR antagonism also prevented accurate quantification. Though further investigation is required for neurochemistry, my findings suggest that NMDAR hypofunction model does recapitulate certain sex differences seen in schizophrenia and is a promising model for examining their biological bases and developing novel, effective treatments for overcoming this devastating disorder.